Imprint switch mutations at Rasgrf1 support conflict hypothesis of imprinting and define a growth control mechanism upstream of IGF1

Nadia M. Drake, Yoon Jung Park, Aditya S. Shirali, Thomas A. Cleland, Paul D. Soloway

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31 Scopus citations


Rasgrf1 is imprinted and expressed preferentially from the paternal allele in neonatal mouse brain. At weaning, expression becomes biallelic. Using a mouse model, we assayed the effects of perturbing imprinted Rasgrf1 expression in mice with the following imprinted expression patterns: monoallelic paternal (wild type), monoallelic maternal (maternal only), biallelic (both alleles transcribed), and null (neither allele transcribed). All genotypes exhibit biallelic expression around weaning. Consequences of this transient imprinting perturbation are manifested as overall size differences that correspond to the amount of neonatal Rasgrf1 expressed and are persistent, extending into adulthood. Biallelic mice are the largest and overexpress Rasgrf1 relative to wild-type mice, null mice are the smallest and underexpress Rasgrf1 as neonates, and the two monoallelically expressing genotypes are intermediate and indistinguishable from one another, in both size and Rasgrf1 expression level. Importantly, these data support one of the key underlying assumptions of the "conflict hypothesis" that describes the evolution of genomic imprinting in mammals and supposes that equivalent amounts of imprinted gene expression produce equivalent phenotypes, regardless of which parental allele is transcribed. Concordant with the difference in overall body size, we identify differences in IGF-1 levels, both in serum protein and as liver transcript, and identify additional differential expression of components upstream of IGF-1 release in the GH/IGF-1 axis. These data suggest that imprinted Rasgrf1 expression affects GH/IGF-1 axis function, and that the consequences of Rasgrf1 inputs to this axis persist beyond the time period when expression is restricted via epigenetic mechanisms, suggesting that proper neonatal Rasgrf1 expression levels are critical for development.

Original languageEnglish
Pages (from-to)654-663
Number of pages10
JournalMammalian Genome
Issue number9-10
StatePublished - Oct 2009

Bibliographical note

Funding Information:
We thank Loren DeVito for her initial observations; Dr. Yves Boisclair and Ruqian Zhao for helpful discussions and input; and the Mouse Metabolic Phenotyping Centers at the University of Cincinnati and Vanderbilt University. Funding was from Cornell University Presidential Genomics Fellowship, NIH Training Grant T32DK007158 to Cornell University, Division of Nutritional Sciences, and R01CA098597 to PDS.


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